tbuckley/cabot-search huggingface dataset:
CD150-dependent hematopoietic stem cell sensing of <i>Brucella</i> instructs myeloid commitment
Authors: Lisiena Hysenaj, Bérengère de Laval, Vilma Arce-Gorvel, Mile Bosilkovski, Gabriela González-Espinoza, Guilhaume Debroas, Michael H. Sieweke, Sandrine Sarrazin, Jean-Pierre Gorvel
Journal: The Journal of Experimental Medicine (2023)

So far, hematopoietic stem cells (HSC) are considered the source of mature immune cells, the latter being the only ones capable of mounting an immune response. Recent evidence shows HSC can also directly sense cytokines released upon infection/inflammation and pathogen-associated molecular pattern interaction while keeping a long-term memory of previously encountered signals. Direct sensing of danger signals by HSC induces early myeloid commitment, increases myeloid effector cell numbers, and contributes to an efficient immune response. Here, by using specific genetic tools on both the host and pathogen sides, we show that HSC can directly sense B. abortus pathogenic bacteria within the bone marrow via the interaction of the cell surface protein CD150 with the bacterial outer membrane protein Omp25, inducing efficient functional commitment of HSC to the myeloid lineage. This is the first demonstration of direct recognition of a live pathogen by HSC via CD150, which attests to a very early contribution of HSC to immune response.
Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Reza Mirzaei, Charlotte D'Mello, Marina Liu, Ana Nikolic, Mehul Kumar, Frank Visser, Pinaki Bose, Marco Gallo, V. Wee Yong
Journal: Cancer Research (2023)

Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs could provide insights into the role of the brain tumor microenvironment in regulating intratumoral heterogeneity. Here, we performed spatial transcriptomic and single-cell analyses of the mouse and human GBM microenvironment to dissect the impact of distinct anatomical regions of brains on GBM. In a syngeneic GBM mouse model, spatial transcriptomics revealed that numerous extracellular matrix (ECM) molecules, including biglycan, were elevated in areas infiltrated with brain tumor-initiating cells (BTIC). Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing showed that ECM molecules were differentially expressed by GBM cells based on their differentiation and cellular programming phenotypes. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, which was associated mechanistically with low-density lipoprotein receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs developed into larger tumors and displayed mesenchymal phenotypes when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in GBM and suggests that the biglycan-LRP6 axis could be a therapeutic target to curb tumor growth.Characterization of the spatial heterogeneity of glioblastoma identifies regulators of brain tumor-initiating cells and tumor growth that could serve as candidates for therapeutic interventions to improve the prognosis of patients.
Accuracy of Self-assessment of Gestational Duration Among Adolescents Seeking Abortion Using Information in Addition to Date of Last Menstrual Period
Authors: Lauren Ralph, M. Antonia Biggs, Katherine Ehrenreich, Daniel Grossman
Journal: JAMA Pediatrics (2023)

This diagnostic study evaluates whether using additional information beyond the date of last menstrual period is associated with improved accuracy of self-assessed gestational duration among adolescents seeking abortion.
Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With <i>BRCA</i>-Mutated Ovarian Cancer
Authors: Yoo-Na Kim, Yeeun Shim, Jieun Seo, Zisun Choi, Yong Jae Lee, Saeam Shin, Sang Wun Kim, Sunghoon Kim, Jong Rak Choi, Jung-Yun Lee, Seung-Tae Lee
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Patient-specific molecular alterations leading to PARP inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in postprogression treatment response and survival. Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated. Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in 1 and 3 patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased postprogression on PARPis, showing at least one postspecific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms—homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040). Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving postprogression treatment and survival.
Overcome Health Inequities to Eliminate Viral Hepatitis
Authors: Ronald O. Valdiserri, Howard K. Koh, John W. Ward
Journal: JAMA (2023)

This Viewpoint outlines the progress made toward eliminating hepatitis B and C but emphasizes the work that remains to prioritize diagnosis and treatment of populations disproportionately affected by viral hepatitis, including ensuring that there are systems in place to treat those infected and care for those at risk.
Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy
Authors: Yansong Tang, Mengying Feng, Yang Su, Teng Ma, Hongjie Zhang, Hongchun Wu, Xiaoyu Wang, Shuyue Shi, Ying Zhang, Yawei Xu, Shijun Hu, Ke Wei, Dachun Xu
Journal: Circulation (2023)

A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.
Ichthyotic skin phenotype induced by the chronic activation of Toll-like receptor 2, and autoinflammation
Authors: Takuya Takeichi, Yoshinao Muro, Masashi  Akiyama
Journal: British Journal of Dermatology (2023)

We read with great interest ‘Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype’ by Tagoe et al.1 Their findings expand our recent understanding of how certain kinds of autoinflammation contribute to the pathogenesis of ichthyosis. Inspired by the report by Tagoe et al., we suggest that their unique autosomal recessive congenital ichthyosis in vitro models have several characteristics in common with autoinflammatory keratinization diseases.
Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: Insights from the <scp>EMPEROR‐Preserved</scp> trial
Authors: Abhinav Sharma, João Pedro Ferreira, Faiez Zannad, Stuart J. Pocock, Gerasimos Filippatos, Egon Pfarr, Michaela Petrini, Bettina J. Kraus, Christoph Wanner, Milton Packer, Javed Butler, Stefan D. Anker
Journal: European Journal of Heart Failure (2023)

In the EMPEROR-Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure (HF) with preserved ejection fraction. In this pre-specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or urine albumin to creatinine ratio >300 mg/g). The primary and key secondary outcomes were (i) a composite of cardiovascular death or first HF hospitalization (primary outcome); (ii) total number of HF hospitalization, (iii) eGFR slope; and a pre-specified exploratory composite kidney outcome including a sustained ≥40% decline in eGFR, chronic dialysis or renal transplant. The median follow-up was 26.2 months. A total of 5988 patients were randomized to empagliflozin or placebo, of whom 3198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD: hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.94; without CKD: HR 0.75, 95% CI 0.60-0.95; interaction p = 0.67) and total (first and recurrent) hospitalizations for HF (with CKD: HR 0.68, 95% CI 0.54-0.86; without CKD: HR 0.89, 95% CI 0.66-1.21; interaction p = 0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01-1.85) ml/min/1.73 m2 /year in patients with CKD and 1.31 (0.88-1.74) ml/min/1.73 m2 /year in patients without CKD (interaction p = 0.70). Empagliflozin did not reduce the pre-specified kidney outcome in patients with or without CKD (with CKD: HR 0.97, 95% CI 0.71-1.34; without CKD: HR 0.92, 95% CI 0.58-1.48; interaction p = 0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across five baseline eGFR categories (all interaction p >0.05). Empagliflozin was well tolerated independent of CKD status.In EMPEROR-Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73 m2 .
Dynamic Evolution of Retroviral Envelope Genes in Egg-Laying Mammalian Genomes
Authors: Koichi Kitao, Hiyori Shoji, Takayuki Miyazawa, So Nakagawa
Journal: Molecular Biology and Evolution (2023)

Abstract Independently acquired envelope (env) genes from endogenous retroviruses have contributed to the placental trophoblast cell–cell fusion in therian mammals. Egg-laying mammals (monotremes) are an important sister clade for understanding mammalian placental evolution, but the env genes in their genomes have yet to be investigated. Here, env-derived open reading frames (env-ORFs) encoding more than 400 amino acid lengths were searched in the genomes of two monotremes: platypus and echidna. Only two env-ORFs were present in the platypus genome, whereas 121 env-ORFs were found in the echidna genome. The echidna env-ORFs were phylogenetically classified into seven groups named env-Tac1 to -Tac7. Among them, the env-Tac1 group contained only a single gene, and its amino acid sequence showed high similarity to those of the RD114/simian type D retroviruses. Using the pseudotyped virus assay, we demonstrated that the Env-Tac1 protein utilizes echidna sodium-dependent neutral amino acid transporter type 1 and 2 (ASCT1 and ASCT2) as entry receptors. Moreover, the Env-Tac1 protein caused cell–cell fusion in human 293T cells depending on the expression of ASCT1 and ASCT2. These results illustrate that fusogenic env genes are not restricted to placental mammals, providing insights into the evolution of retroviral genes and the placenta.
Lowering serum urate level to a guideline‐based target is associated with a lower risk of incident fracture in people with gout: comment on the article by Wei et al
Authors: Gang Wang, Ning Zhuo, Dong Yan, Zhichun Liu
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression
Authors: Maxime Janin, Manel Esteller
Journal: Blood Cancer Discovery (2023)

Summary: Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., p. 228 (8) .
Contemporary insights into the epidemiology, impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum
Authors: Gregor Heitzinger, Noemi Pavo, Sophia Koschatko, Charlotte Jantsch, Max‐Paul Winter, Georg Spinka, Varius Dannenberg, Stefan Kastl, Suriya Prausmüller, Henrike Arfsten, Carolina Dona, Christian Nitsche, Kseniya Halavina, Matthias Koschutnik, Katharina Mascherbauer, Cornelia Gabler, Guido Strunk, Christian Hengstenberg, Martin Hülsmann, Philipp E. Bartko, Georg Goliasch
Journal: European Journal of Heart Failure (2023)

Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision-making.
A machine learning‐derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: Findings from the <scp>HOMAGE</scp> trial
Authors: Masatake Kobayashi, Olivier Huttin, João Pedro Ferreira, Kevin Duarte, Arantxa González, Stephane Heymans, Job A.J. Verdonschot, Hans‐Peter Brunner‐La Rocca, Pierpaolo Pellicori, Andrew L. Clark, Johannes Petutschnigg, Frank Edelmann, John G. Cleland, Patrick Rossignol, Faiez Zannad, Nicolas Girerd
Journal: European Journal of Heart Failure (2023)

An echocardiographic algorithm derived by machine learning (e'VM) characterizes pre-clinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone.The HOMAGE (Heart OMics in AGEing) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74 ± 7 years, 25% women) with available echocardiographic variables (i.e. e' mean, left ventricular end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes. A majority (>80%) had either a 'diastolic changes' (D), or 'diastolic changes with structural remodelling' (D/S) phenotype. The D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p < 0.05). Spironolactone significantly reduced E/e' and B-type natriuretic peptide (BNP) levels in the D/S phenotype (p < 0.01), but not in other phenotypes (p > 0.10; pinteraction <0.05 for both). These interactions were not observed when considering guideline-recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in the D/S phenotype than the D phenotype but the interaction test did not reach significance.In the HOMAGE trial, the e'VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e' and BNP.
iPSC Models of Leukemia Come of Age
Authors: Sergei Doulatov
Journal: Blood Cancer Discovery (2023)

In this issue of Blood Cancer Discovery, Kotini and colleagues present a strategy for large-scale reprogramming of primary human acute myeloid leukemias (AML) to induced pluripotent stem cell (iPSC). They show that the hematopoietic differentiation of AML iPSCs gives rise to transplantable leukemias with remarkable molecular similarity to the original patients' AML, providing new models and insights into the disease. See related article by Kotini et al., p. 318 (7) .
GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1
Authors: Seeyoung Choi, Teri Hatzihristidis, Guillaume Gaud, Avik Dutta, Jan Lee, Awadhesh Arya, Lauren M. Clubb, Daniel B. Stamos, Adrienn Markovics, Katalin Mikecz, Paul Love
Journal: The Journal of Experimental Medicine (2023)

The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS-GRB2-SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis-/- thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4+CD8+ thymocytes to low affinity positively selecting self-ligands.
Sodium and potassium changes during decongestion with acetazolamide – A pre‐specified analysis from the <scp>ADVOR</scp> trial
Authors: Sebastiaan Dhont, Pieter Martens, Evelyne Meekers, Jeroen Dauw, Frederik H. Verbrugge, Petra Nijst, Jozine M. ter Maaten, Kevin Damman, Alexandre Mebazaa, Gerasimos Filippatos, Frank Ruschitzka, W.H. Wilson Tang, Matthias Dupont, Wilfried Mullens
Journal: European Journal of Heart Failure (2023)
Good Habits Do Not Necessarily Help Childhood Constipation
Authors: Mitchell B. Cohen, Carlo Di Lorenzo
Journal: JAMA Pediatrics (2023)

To the Editor We read with interest the JAMA Pediatrics Patient Page entitled, “What Parents Should Know About Constipation in Children.”1 We agree with the relevance of the topic and handout. However, we would like to point out examples of disagreement in the article.
A Modified Small Intestinal Submucosa Patch with Multifunction to Promote Scarless Repair and Reinvigoration of Urethra
Authors: Li‐Ping Huang, Yuan Liu, Qian‐Jin Li, Wen‐Qian Zhang, Chen‐Yu Wu, Long‐Mei Zhao, Hui‐Qi Xie
Journal: Advanced Healthcare Materials (2023)

To reconstruct and restore the functions of the male urethra is a challenging task for urologists. The acellular matrix graft currently used in the clinics is mono-functional and may cause a series of complications including stricture, fibrosis, and stone formation. As a result, such graft materials cannot meet the increasing demand for multifunctionality in the field of urethral tissue engineering. In this context, a multifunctional urethral patch is designed for the repair of urethral defects by mixing protocatechualdehyde (PCA) with small intestinal submucosa (SIS) under an alkalin condition to allow cross linking. As shown, the PCA/SIS patch possesses excellent biocompatibility, antioxidant activity, and anti-inflammatory property. More importantly, this patch can remarkably promote the adhesion, proliferation, and directional extension of rabbit bladder epithelial mucous cells (R-EMCs) as well as rabbit bladder smooth muscle cells (R-SMCs), and upregulate the expression of cytokeratin in the EMCs and contractile protein in the SMCs in vitro. In vivo experiments also confirm that the PCA/SIS patch can significantly enhance scarless repair of urethral defects in rabbits by facilitating smooth muscle regeneration, reducing excessive collagen deposition, and accelerating re-epithelialization and neovascularization. Taken together, the newly developed multifunctional PCA/SIS patch provides a promising candidate for urethral regeneration.